A common genetic abnormality associated with malignant myeloid neoplasms in humans is the loss of whole chromosome 5 or 7 or a deletion of the long arm 5q or 7q of one of these chromosomes. In one reported study of 129 patients with therapy-related myelodisplastic syndrome (t-MDS) or therapy-related acute myeloid leukemia (t-AML), 75% of the patients had a loss or deletion of chromosome 5 or 7 (LeBeau). In addition, a deletion in 5q has also been observed in 10% of patients with AML arising de novo, and in 15% of patients who have MDS arising de novo (Nimer).
The 5q human chromosome region is known to contain a number of genes encoding growth factors, hormone receptors, and proteins involved in signal transduction or transcriptional regulation, and several of these genes are good candidates for tumor suppressor genes. The LeBeau study cited above investigated the possibility that deletion of a particular one or more of these genes, including the hematopoietic growth factors CSF2, IL3, IL4, IL5, and IL9, as well as EGR1, might be responsible for the predisposition to malignant myeloid neoplasms. The study was unsuccessful in identifying such a gene.
It has now been discovered, in accordance with the present invention, that at least one of the genes whose deletion in the 5q chromosome region correlates strongly with leukemia is a gene which is herein identified as a human RAD50 (hRAD50) gene, analogous to RAD50 gene in the yeast Saccharomyces cerevisiae (Sc).
In yeast, RAD50 is one of an epistatic group of genes whose products have been implicated in the recombinational repair of double-strand breaks (DSB's). The group of yeast genes include RAD50-57, MRE2, MRE11, XRS2, and RFA1 (Hays). Studies to date suggest that several genes in the group form a multi-protein complex (or complexes) that function in DSB repair, and participate in meiotic recombinational events (Firmenich, Hays).
Sc RAD50 itself appears to be required for recombinational repair of many types of DSB's (Tran), possibly in a complex with MRE11 (Johzuka, Ivanov). RAD50 functions in Sc is required during vegetative growth for recombinational repair of DSB, and during meiosis, for initiation of meiotic recombination (Raymond, 1993a). In light of the key role played by the protein, and the fact that the protein is known to bind to DNA in the presence of ATP (Raymond, 1993b), it has been proposed that the protein functions in chromosomal homology searching between interacting DNA molecules (Alani, 1989; 1990).